Halosteroid and preparation of the same



Patented Mar. 7, 1944 UNITED STATES PATEN FF CE;

HALOSTEROID AND PREPARATION OF THE SAME Russell Earl Marker, State College, Pa... and Harry M. Crooks, Jr., Detroit, Mich., assignors to Parke, Davis & Company, Detroit, Micln, a corporation of Michigan No Drawing. Original application September 4, 1941, Serial No. 409,590. Divided and this application September 28, 1942, Serial No. 460,000

6 Claims. c1. zen-397.4)

mula

([3113 C113 C=O ZX L.

where X is chlorine or bromine. These 16,17-diha1o-20-keto-pregnane compounds are prepared by the reaction of chlorine or bromine on A keto-pregnene compounds. This reaction takes place quickly and smoothly at room temperature, or indeed, below room temperature, and a catalyst is not necessary. It is preferable to conduct the reaction in a solvent inert to elementary halogen, such as acetic acid, carbon tetrachloride, nitrobenzene, etc. I

The reaction is illustrated by the following diagram:

CH3 =0 \I B/ l X:

The above transformation in ring D takes" place regardless of the nature of the substitutes in rings A, B and C of the A -20-keto-pregnene compound which is halogenated. This does not imply, however, that rings A, B and C are necessarily unaffected during the halogenation, for if certain reactive groupings, such as carbon-tocarbon double bonds or ketone groupings, are present in rings A, B and C, the halogen may act at these points as well as on the structural groupms t ring The chemical reactions of the 16,l7-dihalo-20- keto-pregnane compounds are closely analogous to the reactions of the 17,21-dihalo-20-keto- 'pr'egnane compounds:

The transformation of a 16,17-dihalo-20-ket0- pregnane compound into the A -2l-pregnenoic acid is best effected by an excess of strong alcoholic alkali. For example, there may be used 'methanolic potassium hydroxide, ethanolic sodium hydroxide or a solution of sodium in propyl alcohol. There is also frequently formed, besides the A -21-pregnenoic acid, a relatively small amount of the ester of the A -21-pregnenoic acid and the alcohol used as a solvent.

The action of dehydrogenating agents on 16,17- dihalo-20-keto-pregnane compounds leads to the formation of A -unsaturated-20-keto-pregnane compounds. Dehalogenati'ng agents which operate satisfactorily in this reaction includezinc and acetic acid or alcohol, sodium iodide in alcohol or acetone, and hydrogen in the presence of palladium and pyridine.

Surprisingly, dehydrohalogenating agents also react with 16,17-dihalo-20-keto-pregnane compounds to form A -unsaturated-20-keto-pregnene compounds. Dehydrohalogenating agents operative in this manner include potassium acetate in acetic acid and also pyridine.

The invention is further illustrated by the following example:

EXAMPLE A. 16,17-DIBROMO-PREGNANOL-3(fl) -0NE-2O ACETATE To a solution of 5 g. of A -pregnenol-3(fi) -one 20 acetate in 200 cc. of acetic acid is added 14 cc. of a 1 M. solution of bromine in acetic acid. Then the mixture is diluted with water and the precipitated solid collected and crystallized from methanol. The product, M. P. 137-140" 0., gives the following analysis:

Anal. calcd. for C23H34O3B12: C, 53.3; H, 6.6. Found: C, 53.5; H, 6.7.

These analytical figures correspond to a di- AcOV V I B. REACTION or METHANOLIC POTASSIUM HYnRox- VIDE WITH 16,17-D1BR0M0-PRE NANL-3is)-oNr:-

'ZQACETATE v A: solution of g. of 16,1'7-dibromo-pregnano1-- 3()-0ne-20 acetate and g. of potassium hydroxide in 1 liter of methanol is refluxed for one hour. Then water is added and the mixture is extracted with ether. In this way there is obtained two fractions which may be designated the aqueous alkaline phase and "the neutral ethereal phase. These two fractions are worked up as follows:

a. The aqueous alkaline phase.The aqueous alkaline phase is acidified with dilute hydrochloric acid and extracted with ether. The ethereal solution is washed with water and evaporated to dryness. The crystalline residue is recrystallized from methanol to give 3(B)-hydroxy-A"-2lpregnenoic acid of M. P. 254-256 C. dec.

b. The neutral ethereal phase.The neutral ethereal extract is evaporated to dryness and the crystalline residue is recrystallized from methanol. Thus ther is obtained methyl 3(B)-hydroxy-A 21-pregnenoate of M. P. 153-156" C.

What we claim as our invention is:

1.- Process for the preparation of a halosteroid having at ring D the probable structure I CHa C=O D where X is a member of the class consisting -of chlorine and bromine which comprises reacting a steroid having at ring D the structure with a member of the class consisting of chlorine and bromine. U

2. Process for the preparation of ahalosteroid of the formula where X is a member of the class consisting of C1 and Br and R. is a member of the class consisting of OH' and groups hydroly zable to OH which comprises'reactin'ga steroid of the formula CH3 CH3 CH3 with a halogenating agent of the class consisting of chlorine and bromine.

3. Process for the preparation of a halosteriod of the formula with bromine.

4. A halosteriod having in ring D the formula 0 CH3 e=o where X is a member of the class consisting of "Cland'Br. 5. A halosteriod having the formula 1: cm 0113' (3H3 0:0 ()0 f X J where X is a member of the class consisting of Cl and Br and R is a member of 'the class consisting of --OH and groups hydrolyzable to 6. A halosteriod of the formula CH3 CH3 CH3 0:0 as 4Br A r AcOL/ RUSSELL EARL MARKER; HARRY M. cRooKs. JR, 3 

